TY - JOUR
T1 - Crystal Structures of Metallo-β-Lactamase (IMP-1) and Its D120E Mutant in Complexes with Citrate and the Inhibitory Effect of the Benzyl Group in Citrate Monobenzyl Ester
AU - Yamaguchi, Yoshihiro
AU - Kato, Koichi
AU - Ichimaru, Yoshimi
AU - Jin, Wanchun
AU - Sakai, Misa
AU - Abe, Miki
AU - Wachino, Jun Ichi
AU - Arakawa, Yoshichika
AU - Miyagi, Yukina
AU - Imai, Masanori
AU - Fukuishi, Nobuyuki
AU - Yamagata, Yuriko
AU - Otsuka, Masami
AU - Fujita, Mikako
AU - Kurosaki, Hiromasa
N1 - Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/7/22
Y1 - 2021/7/22
N2 - The emergence and rapid spread of carbapenem-resistant pathogens producing metallo-β-lactamases such as IMP-1 and NDM-1 have been of great concern in the global clinical setting. The X-ray crystal structures of IMP-1 fromSerratia marcescensand its single mutant, D120E, in complexes with citrate were determined at resolutions of 2.00 and 1.85 Å, respectively. Two crystal structures indicate that a single mutation at position 120 caused a structural change around Zn1, where the geometry changes from a tetrahedron in the native IMP-1 to a square pyramid in D120E. Based on these two complex structures, the authors synthesized citrate monobenzyl ester 1 to evaluate the structural requirement for the inhibitory activity against IMP-1 and compared the inhibitory activities with nonsubstituted citrate. The introduction of a benzyl group into citrate enhanced the inhibitory activity in comparison to citrate (IC50> 5 mM).
AB - The emergence and rapid spread of carbapenem-resistant pathogens producing metallo-β-lactamases such as IMP-1 and NDM-1 have been of great concern in the global clinical setting. The X-ray crystal structures of IMP-1 fromSerratia marcescensand its single mutant, D120E, in complexes with citrate were determined at resolutions of 2.00 and 1.85 Å, respectively. Two crystal structures indicate that a single mutation at position 120 caused a structural change around Zn1, where the geometry changes from a tetrahedron in the native IMP-1 to a square pyramid in D120E. Based on these two complex structures, the authors synthesized citrate monobenzyl ester 1 to evaluate the structural requirement for the inhibitory activity against IMP-1 and compared the inhibitory activities with nonsubstituted citrate. The introduction of a benzyl group into citrate enhanced the inhibitory activity in comparison to citrate (IC50> 5 mM).
UR - https://www.scopus.com/pages/publications/85111145238
UR - https://www.scopus.com/inward/citedby.url?scp=85111145238&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c00308
DO - 10.1021/acs.jmedchem.1c00308
M3 - Article
C2 - 34242022
AN - SCOPUS:85111145238
SN - 0022-2623
VL - 64
SP - 10019
EP - 10026
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 14
ER -